The rat as a model physiological system

Guyader, Dominique

doi:10.1002/047001153x.g204205

Cited by 6 publications

(7 citation statements)

References 81 publications

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“…Previous studies have shown that miRNAs regulate various physiological events relevant to T2D pathophysiology, such as insulin secretion, insulin responsiveness and energy homeostasis. Here, we have characterized differential miRNA and mRNA expression in insulin sensitive tissues of rats of a model of T2D (GK rat) and in normoglycaemic BN controls, a strain combination extensively used to study the genetic determinants of T2D phenotypes in F2 hybrids and congenic strains [ 21 ]. In the miRNA data, the most striking finding was the over-expression of miR-125a in both liver and adipose tissue (with nearly 6-fold and 2-fold higher expression, respectively) in GK compared to BN rats.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, we aim to identify differential liver and adipose tissue miRNA expression in rats of the GK strain and a genetically distant normoglycaemic strain (Brown-Norway (BN)). The GK strain is extensively used to study genetic determinants of T2D phenotypes [ 21 ], while the BN strain is widely used for comparison with GK and most congenic strains with a BN background. Additionally, we assessed mRNA expression levels in the same tissues from the same rats to investigate the downstream effects of altered miRNA expression on target gene expression; the approach is illustrated in additional File 1 [Additional file 1 ].…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-125a is over-expressed in insulin target tissues in a spontaneous rat model of Type 2 Diabetes

et al. 2009

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Background: MicroRNAs (miRNAs) are non-coding RNA molecules involved in posttranscriptional control of gene expression of a wide number of genes, including those involved in glucose homeostasis. Type 2 diabetes (T2D) is characterized by hyperglycaemia and defects in insulin secretion and action at target tissues. We sought to establish differences in global miRNA expression in two insulin-target tissues from inbred rats of spontaneously diabetic and normoglycaemic strains.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MicroRNA-125a is over-expressed in insulin target tissues in a spontaneous rat model of Type 2 Diabetes

et al. 2009

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“…The wealth of phenotypic information that can be collected in inbred strains of the laboratory rat makes it a powerful tool for genetic studies of quantitative traits underlying complex phenotypes [5] . Related quantitative trait loci (QTL) identified in crosses derived from different disease rat strains often cluster [6] , [7] , suggesting that a proportion of genetic variants isolated in strains selectively bred for different pathologies (type 2 diabetes, hypertension, obesity) are common and underlie shared pathophysiological mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Pathophysiological, Genetic and Gene Expression Features of a Novel Rodent Model of the Cardio-Metabolic Syndrome

et al. 2008

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BackgroundComplex etiology and pathogenesis of pathophysiological components of the cardio-metabolic syndrome have been demonstrated in humans and animal models.Methodology/Principal FindingsWe have generated extensive physiological, genetic and genome-wide gene expression profiles in a congenic strain of the spontaneously diabetic Goto-Kakizaki (GK) rat containing a large region (110 cM, 170 Mb) of rat chromosome 1 (RNO1), which covers diabetes and obesity quantitative trait loci (QTL), introgressed onto the genetic background of the normoglycaemic Brown Norway (BN) strain. This novel disease model, which by the length of the congenic region closely mirrors the situation of a chromosome substitution strain, exhibits a wide range of abnormalities directly relevant to components of the cardio-metabolic syndrome and diabetes complications, including hyperglycaemia, hyperinsulinaemia, enhanced insulin secretion both in vivo and in vitro, insulin resistance, hypertriglyceridemia and altered pancreatic and renal histological structures. Gene transcription data in kidney, liver, skeletal muscle and white adipose tissue indicate that a disproportionately high number (43–83%) of genes differentially expressed between congenic and BN rats map to the GK genomic interval targeted in the congenic strain, which represents less than 5% of the total length of the rat genome. Genotype analysis of single nucleotide polymorphisms (SNPs) in strains genetically related to the GK highlights clusters of conserved and strain-specific variants in RNO1 that can assist the identification of naturally occurring variants isolated in diabetic and hypertensive strains when different phenotype selection procedures were applied.ConclusionsOur results emphasize the importance of rat congenic models for defining the impact of genetic variants in well-characterised QTL regions on in vivo pathophysiological features and cis-/trans- regulation of gene expression. The congenic strain reported here provides a novel and sustainable model for investigating the pathogenesis and genetic basis of risks factors for the cardio-metabolic syndrome.

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“…A broad range of experimental mammalian systems developed in the laboratory mouse (Buchner and Nadeau 2015) and rat (Gauguier 2005) allow the collection of organs from large cohorts of individuals maintained in strictly standardized conditions, thus limiting interindividual phenotype variability, and provide powerful tools for eQTL mapping. The inbred Goto–Kakizaki (GK) rat model of type 2 diabetes mellitus was produced over many generations of breeding rats from an outbred Wistar stock, using glucose intolerance as the sole criterion for selecting breeders (Goto et al 1976).…”

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Transcriptome Profiling in Rat Inbred Strains and Experimental Cross Reveals Discrepant Genetic Architecture of Genome-Wide Gene Expression

Kaisaki

Otto

Argoud

et al. 2016

G3 Genes|Genomes|Genetics

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To test the impact of genetic heterogeneity on cis- and trans-mediated mechanisms of gene expression regulation, we profiled the transcriptome of adipose tissue in 20 inbred congenic strains derived from diabetic Goto–Kakizaki (GK) rats and Brown–Norway (BN) controls, which contain well-defined blocks (1–183 Mb) of genetic polymorphisms, and in 123 genetically heterogeneous rats of an (GK × BN)F2 offspring. Within each congenic we identified 73–1351 differentially expressed genes (DEGs), only 7.7% of which mapped within the congenic blocks, and which may be regulated in cis. The remainder localized outside the blocks, and therefore must be regulated in trans. Most trans-regulated genes exhibited approximately twofold expression changes, consistent with monoallelic expression. Altered biological pathways were replicated between congenic strains sharing blocks of genetic polymorphisms, but polymorphisms at different loci also had redundant effects on transcription of common distant genes and pathways. We mapped 2735 expression quantitative trait loci (eQTL) in the F2 cross, including 26% predominantly cis-regulated genes, which validated DEGs in congenic strains. A hotspot of >300 eQTL in a 10 cM region of chromosome 1 was enriched in DEGs in a congenic strain. However, many DEGs among GK, BN and congenic strains did not replicate as eQTL in F2 hybrids, demonstrating distinct mechanisms of gene expression when alleles segregate in an outbred population or are fixed homozygous across the entire genome or in short genomic regions. Our analysis provides conceptual advances in our understanding of the complex architecture of genome expression and pathway regulation, and suggests a prominent impact of epistasis and monoallelic expression on gene transcription.

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The rat as a model physiological system

Cited by 6 publications

References 81 publications

MicroRNA-125a is over-expressed in insulin target tissues in a spontaneous rat model of Type 2 Diabetes

MicroRNA-125a is over-expressed in insulin target tissues in a spontaneous rat model of Type 2 Diabetes

Pathophysiological, Genetic and Gene Expression Features of a Novel Rodent Model of the Cardio-Metabolic Syndrome

Transcriptome Profiling in Rat Inbred Strains and Experimental Cross Reveals Discrepant Genetic Architecture of Genome-Wide Gene Expression

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